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Studies on Interaction of Buffalo Brain Cystatin with Donepezil: An Alzheimer's Drug

DOI: 10.1155/2013/842689

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Abstract:

When drugs bind to a protein, the intramolecular structures can be altered, resulting in conformational change of the protein. Donepezil, an Acetyl Cholinesterase inhibitor (AChE), is commonly prescribed to patients with Alzheimer's disease (AD) to enhance cholinergic neurotransmission. It is the “first-line” agents in the treatment of Alzheimer's disease used to improve cognitive function in the disease. In the present study, a cysteine protease inhibitor (cystatin) has been isolated from buffalo brain using alkaline treatment, 40 to 60% ammonium sulphate fractionation and gel filtration chromatography on Sephadex G-75 with % yield of 64.13 and fold purification of 384.7. The purified inhibitor (Buffalo Brain Cystatin, (BBC)) was eluted as a single papain inhibitory peak which migrated as single band on native PAGE; however, on SDS-PAGE with and without beta mercaptoethanol (βME) BBC gave two bands of M W 31.6 and 12.4?KDa, respectively. The molecular weight determined by gel filtration came out to be 43.6?KDa. The UV spectra of cystatin on interaction with donepezil suggested a conformational change in the protein. The fluorescence spectra of BC-donepezil composite show structural changes indicating 40?nm red shift with significant increase in fluorescence intensity of cystatin in the presence of donepezil representing an unfolding of cystatin on interaction, which is an indication of side effect of donepezil during the use of this drug. 1. Introduction Brain is exposed to a variety of neuromodulating agents given as therapy. The effect of these agents apart from generation of desired activity must be assessed to understand the mechanism of action and side effects of the drug if any. Alzheimer is the most common cause of dementia; it is a primary degenerative disease of the brain. Onset is usually late in life with increasing impairment of memory, cognition, linguistic ability, and judgment. It is a progressive brain disorder that gradually destroys a person’s ability to learn, reason, and carry out daily activities [1, 2]. Acetylcholine is an important neurotransmitter associated with normal functioning of the brain. The greatly reduced concentration of acetylcholine in the cerebral cortex is a significant factor in AD [3, 4]. People with Alzheimer disease (AD) have lower level of acetylcholine with the development of abnormalities in cholinergic neurons. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine (Ach) by blocking the relevant enzyme AchE (acetyl choline esterase) [2] (Figure 1). Figure

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